CD109 release from the cell surface in human keratinocytes regulates TGF-β receptor expression, TGF-β signalling and STAT3 activation: relevance to psoriasis
CD109 release from the cell surface in human keratinocytes regulates TGF-β receptor expression, TGF-β signalling and STAT3 activation: relevance to psoriasis
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DOI：
10.1111/j.1600-0625.2011.01288.x
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发表时间：
2011-08-01
影响因子：
3.6
通讯作者：
Philip, Anie
中科院分区：
文献类型：
--
作者：
Litvinov, Ivan V.;Bizet, Albane A.;Philip, Anie
转化生长因子（TGF）-β是负调节角质形成细胞增殖的重要细胞因子。在银屑病中已经报道了TGF-β信号传导的失调，其中尽管TGF-β的表达增加，但银屑病角质形成细胞继续过度增殖。最近，我们已经确定了CD 109，糖基磷脂酰肌醇（GPI）锚定蛋白，作为一种新的共受体和TGF-β信号负调节。在目前的工作中，我们证明了从细胞表面释放CD 109或添加CD 109蛋白导致人角质形成细胞中TGF-β信号转导和TGF-β受体表达下调。此外，这些作用与磷酸化STAT 3水平的增加、增强的总STAT 3和Bcl-2表达以及细胞生长和存活的增加相关，表明释放的/可溶性CD 109能够诱导已知在银屑病中发生的分子变化。银屑病患者中CD 109表达的分析揭示，与邻近未受累皮肤相比，银屑病表皮中CD 109蛋白表达显著降低。相反，与正常皮肤相比，银屑病斑块中CD 109 mRNA的表达没有变化。这提出了银屑病角质形成细胞中CD 109蛋白释放增强的可能性。此外，银屑病表皮显示TGF-β受体表达降低，这与在体外释放CD 109或添加CD 109重组蛋白的角质形成细胞中获得的结果一致。总之，我们的研究结果表明，在人类角质形成细胞的细胞表面的异常CD 109释放可能会诱导分子的变化，通常在银屑病中观察到，并可能解释TGF-β受体下调和减少TGF-β信号在银屑病。
Transforming growth factor (TGF)-beta is an important cytokine that negatively regulates keratinocyte proliferation. Deregulation of TGF-beta signalling has been reported in psoriasis, where despite increased expression of TGF-beta, psoriatic keratinocytes continue to hyperproliferate. Recently, we have identified CD109, a glycosyl phosphatidylinositol (GPI)-anchored protein, as a novel co-receptor and negative regulator of TGF-beta signalling. In the current work, we demonstrate that release of CD109 from the cell surface or the addition of CD109 protein results in downregulation of TGF-beta signalling and TGF-beta receptor expression in human keratinocytes. Moreover, these effects are associated with an increase in phospho-STAT3 levels, enhanced total STAT3 and Bcl-2 expression and an increase in cell growth and survival, suggesting that released/soluble CD109 is able to induce molecular changes that are known to occur in psoriasis. Analysis of CD109 expression in psoriasis patients reveals that CD109 protein expression is markedly decreased in psoriatic epidermis as compared to adjacent uninvolved skin. In contrast, CD109 mRNA expression is unchanged in psoriatic plaques in comparison with normal skin. This raises a possibility that CD109 protein release is enhanced in psoriatic keratinocytes. Furthermore, psoriatic epidermis displays decreased expression of TGF-beta receptors, consistent with the results obtained in vitro in keratinocytes with CD109 release or addition of CD109 recombinant protein. Together our findings suggest that aberrant CD109 release from the cell surface in human keratinocytes may induce molecular changes that are usually observed in psoriasis and may explain TGF-beta receptor downregulation and decrease in TGF-beta signalling in psoriasis.